Metabolic Imaging and Molecular Biology Reveal the Interplay between Lipid Metabolism and DHA-Induced Modulation of Redox Homeostasis in RPE Cells

Diabetes-induced oxidative stress induces the development of vascular complications, which are significant causes of morbidity and mortality in diabetic patients. Among these, diabetic retinopathy (DR) is often caused by functional changes in the blood-retinal barrier (BRB) due to harmful oxidative stress events in lipids, proteins, and DNA. Docosahexaenoic acid (DHA) has a potential therapeutic effect against hyperglycemia-induced oxidative damage and apoptotic pathways in the main constituents of BRB, retinal pigment epithelium cells (ARPE-19). Effective antioxidant response elicited by DHA is driven by the activation of the Nrf2/Nqo1 signaling cascade, which leads to the formation of NADH, a reductive agent found in the cytoplasm. Nrf2 also induces the expression of genes encoding enzymes involved in lipid metabolism. This study, therefore, aims at investigating the modulation of lipid metabolism induced by high-glucose (HG) on ARPE-19 cells through the integration of metabolic imaging and molecular biology to provide a comprehensive functional and molecular characterization of the mechanisms activated in the disease, as well the therapeutic role of DHA. This study shows that HG augments RPE metabolic processes by enhancing lipid metabolism, from fatty acid uptake and turnover to lipid biosynthesis and beta-oxidation. DHA exerts its beneficial effect by ameliorating lipid metabolism and reducing the increased ROS production under HG conditions. This investigation may provide novel insight for formulating novel treatments for DR by targeting lipid metabolism pathways.